The lipid composition and distribution of cell membranes play an important role in regulating the physiology of the cell. For example, numerous signaling proteins can be recruited to the membrane by clusters of negatively charged lipids. Live mammalian cells actively maintain an asymmetric lipid distribution on their plasma membrane (see FIG. 1B), with phosphatidylserine (PS), the most abundant anionic lipid, completely confined to the cytosolic leaflet. PS externalization has been observed for cells under abnormal development, including apoptotic cells, activated platelets, and virus-infected cells. In fact, imaging PS exposure has been a benchmark approach to detect apoptotic cells in research laboratories.
Among the limited number of PS-targeting ligands, annexin V is best established for detecting apoptotic cells in vitro and in living organisms. This naturally occurring 36 kDa protein have been labeled with fluoro-chromes or radioactive nuclides and used to studies such as imaging cell death in animal models of human cancer, as well as in humans. However, there are some drawbacks with using annexin V. Annexin V is less ideal as an indicator molecule for the presence of PS because of its large size, high cost, and calcium dependence for PS recognition (see FIG. 2). In addition, the moderate stability and slow clearance severely limit its application in vivo. Small molecules that specifically target PS may circumvent the problems afflicting annexin V and their development has captured increasing attention. There is a class of bivalent organozinc complexes that functionally mimic annexin V and selectively associate with negatively charged membranes. Recently, screening of phage-displayed peptide libraries has also yielded promising lead sequences for PS recognition.